ABSTRACT Cocaine addiction is a chronically relapsing disorder with no current FDA-approved drugs available. A major contributor to relapse is that drug-related stimuli and environments have the ability to powerfully elicit cravings and trigger relapse. Thus, a goal of current treatment plans is to reduce craving evoked by drug-related stimuli. Psychosocial enrichment has been shown to diminish cocaine craving and activation of the medial prefrontal cortex (mPFC) in response to drug-related stimuli, and in a rodent model, environmental enrichment (EE) also reduces cocaine seeking and the ability of drug-related stimuli to activate the mPFC. Despite the robust ability of environmental factors to reduce behavioral and physiological responses to drug stimuli, the mechanisms of this phenomenon are not known. It is possible that EE directly modulates a specific ensemble of neurons that is engaged by exposure to a previous drug-taking environment. One such drug-seeking ensemble resides in the mPFC, a region where enrichment reduces drug stimuli-elicited activity. Our studies will focus on these ensemble neurons to determine if EE affects their ability to become re-activated by exposure to a drug environment, if EE alters cocaine-associated plasticity in these neurons, and if inhibition or excitation of this ensemble alters other mPFC-dependent behaviors.